The broad long-term goal of this project is to develop an optically based radiation biodosimeter that rapidly (~ 15 minutes) measures changes in serological microRNA (miRNA) biomarkers to predict acute radiation syndrome (ARS). MicroRNAs (miRNAs) are short (18-22 base) non- coding RNA strands that control a host of biological processes through regulation of protein expression. Exposure to radiation has been shown to alter expression of a miRNA panels linked with ARS, thereby establishing that serum could be used as a predictive assay for ARS. To measure changes in these miRNA radiation biomarkers, we will develop a MicroRNA-based Radiation Biodosimeter (MiRAD) system, which combines automated magnetic bead based screening for miRNA targets with Amplified Reflectometric Interference Analysis (ARIA), a patented ChromoLogic technology, for highly sensitive and specific quantification of 100s of miRNA radiation biomarkers in parallel. In preliminary studies, we have demonstrated the novel concept of the device and its ability to accurately measure subfemtomolar concentrations of miRNA in ovarian cancer serum samples, 100x less than current RNA quantification platforms such as RT-PCR. Our preliminary studies using rodent plasma also have identified panel of miRNAs with dose and time dependent response to whole body irradiation (WBI), in a dose range relevant to medical triage in case of a radiological event. The hypotheses we seek to validate under the proposed proof-of-concept study are (1) the miRNA panel identified in a murine model through analysis of plasma can be used to measure WBI dose in a clinical setting;(2) a similar miRNA panel can be used to measure WBI dose in nonhuman primates and humans;(3) the resulting identification of a unique and dose-responsive combination of miRNA markers will result in a rapid, POC blood-based microchip assay for anticipating ARS within the first week of exposure, thereby guiding the allocation of exposed subjects for timely medical intervention.

Public Health Relevance

A critical need exists in the area of radiation countermeasures to properly diagnose and treat victims of a nuclear or radiological incident who are at risk for developing acute radiation syndrome (ARS). ChromoLogic proposes to develop the MiRAD technology, which will measure changes in microRNA biomarkers in a patient's blood for diagnosis of ARS. The creation of this predictive diagnostic system will result in earlie and improved treatment allocation, reduced mortality, and provide a means of predicting toxicities in patients undergoing radiotherapy, especially in situations where over- or under-dosing remain a concern.